Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis.
Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses.
Alturki, Norah A.; McComb, Scott; Ariana, Ardeshir; Rijal, Dikchha; Korneluk, Robert G.; Sun, Shao-Cong; Alnemri, Emad S; and Sad, Subash, "Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis." (2018). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 133.
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This article has been peer reviewed. It is the author’s final published version in Cell Death and Disease, Volume 9, Issue 6, June 2018, Article number 592.
The published version is available at https://doi.org/10.1038/s41419-018-0672-0. Copyright © Alturki et al.